Large peptides called chemokines not only orchestrate chemotaxis in immune cells, but also are involved in neurodevelopment and neurophysiological signaling in brain. Chemokines have recently been recognized as essential elements in numerous neurodegenerative diseases and related neuroinflammation. In particular, recruitment of “activated” peripheral blood monocytes containing CCR5 chemokine receptors into atherosclerotic and other types of neuropathological plaques is pivotal to a number of diseases with neuroinflammatory etiologies including HIV and other dementias.
The CCR5 or R5 receptor became the focus of much attention when it was shown to be the essential receptor to which HIV must bind before it enters and infects cells; virtually all “founder” viruses, clones of the actual disease-transmitting virus, use CCR5 exclusively as an entry protein. The drug receptor for DAPTA (D-Ala-Peptide T-amide), the first HIV receptor blocker and entry inhibitor, has been proven to be CCR5 (Polianova, et al., Antiviral Research, 2005).
A number of short enzyme-resistant peptide analogs have been developed which also act as antagonists of CCR2 and CCR5, blocking binding of free HIV envelop proteins (gp120) and receptor signaling, now understood to be causes of immune and CNS inflammatory pathogenesis. Even when plasma HIV is undetectable, the viral “reservoir” of persistently infected cells, now identified as monocytes, continues to release highly potent, receptor active gp120 which drives pathogenesis.
Monomeric DAPTA (M-DAPTA or Adaptavir®) is a third generation HIV receptor blocker antiviral currently in Phase II studies in healthy patients with no detectable HIV-plasma virus as the result of being treated with and maintained on various cocktails of anti-retroviral therapeutics; m-DAPTA, which has been manufactured and formulated to avoid its tendency to form biologically inactive aggregates, has an extremely high (femtomolar range) affinity for R5. The primary endpoint of the ongoing trial is the previously observed (Polianova et al., Peptides, 2003) gradual reduction of infectious virus in white blood cells to undetectable levels in most patients by six months. The secondary endpoints include the serum levels of a number of inflammatory and anti-inflammatory cytokines to replicate a previous clinical study (Ruff, et al., Current HIV Research, 2003) which showed that DAPTA significantly reduced 4 inflammatory cytokines and increased 4 anti-inflammatory cytokines. M-DAPTA, was previously shown to block activated microglial cells and NFkB activation in rats infused intraventricularly with endotoxin (Rosi, et al., Neuroscience, 2005), a model of inflammatory pathogenesis in Alzheimer's Disease.
While disputed by most investigators, the inventors believe their observations make clear that neuroinflammation lies at the root of many diseases of unknown etiology and is initiated in one or more of three ways: 1) viral/microbial infection, 2) tissue trauma/injury or 3) environmental toxin exposure. The actual form the neuroinflammatory disease takes is a function of time and location. With respect to time, inflammation early in pregnancy, for example, can lead to autism; inflammation later in pregnancy, to schizophrenia; and inflammation after 65 years, to Alzheimer's. With respect to location, optic nerve inflammation can lead to demylination in multiple sclerosis; in spinal cord to Lou Gehrig' disease; in the substantia nigra of the brain to Parkinson's disease; in joints, to arthritis, etc.